Simultaneous drug release of two or more therapeutic agents from an intra-vaginal ring (IVR) drug delivery system is challenging because two or more drugs have to be released from one device and a multiple set of pre-defined drug release criteria must be fulfilled in order for the system to be effective. Several different IVR designs have attempted to provide specific controlled release solutions, few have been successful. Most, if not all, of the current IVRs, including those described in the patents and patent applications discussed below, suffer from at least one of the following drawbacks: lack of stability upon storage and transport, inability to independently adjust the release rate of multiple therapeutic components, difficulty or expense in manufacturing, inability to meet necessary release criteria to achieve the desired therapeutic effect.
Examples of known IVRs are described in U.S. Pat. Nos. 3,995,633; 3,995,634; 4,237,885; European patent publication 0,050,867; U.S. Pat. Nos. 4,292,965; 4,596,576; PCT publication WO 97/02015; European Patent 876 815; PCT publication WO2009/036999 and PCT publication WO2004/103336.
Specifically, WO2004/103336 discloses a drug delivery system comprising at least one compartment consisting of (i) a drug-loaded thermoplastic polymer core, (ii) a drug-loaded thermoplastic polymer intermediate layer and (iii) a non-medicated thermoplastic polymer skin covering the intermediate layer, wherein said intermediate layer is loaded with (a) crystals of a first pharmaceutically active compound and with (b) a second pharmaceutically active compound in dissolved form and wherein said core is loaded with said second compound in dissolved form.
Although the system disclosed in WO2004/103336 is suitable for the independent release of many drug combinations, the latter can still be improved upon. All the examples exemplified in WO2004/103336 include a diffusion path through a skin which is identical for all drugs, which are loaded in the skin-enclosed reservoir. The release of the crystalline drug and the dissolved drug loaded in the reservoir is governed by the same skin; hence, by varying skin properties the release of the crystalline drug and the dissolved drug will be tuned in the same direction—both up or both down—and the ratio in which these drugs are released remains essentially unaffected. In the WO2004/103336 delivery system the skin thickness is set to adjust the release of the crystalline drug to the desired level.
Additionally, the IVRs exemplified in WO2004/103336 suffer from the further limitation that the release of the dissolved drug is tuned to its desired rate by dissolving the proper amount in the reservoir. It appears that this specific amount, resulting in the exact concentration needed to obtain the desired release, is directly proportional to the saturation solubility and inversely proportional to the release rate of the crystalline drug. From a mechanistic point of view this is straightforward; low saturation solubility means a small driving force for diffusion and hence higher release rates for the crystalline drug can only be achieved if thin skins are applied. The release of the dissolved drug depends on the amount dissolved and on the thickness of the skin. If the same target release rate for the dissolved drug is to be matched with a thinner skin, less of drug should be dissolved in the core. So, the flipside of applying skins which are too thin is that the amount of dissolved drug becomes too small resulting in early depletion and steeply declining release profiles hampering broad application of the concept disclosed in WO2004/103336.
These phenomena can also be explained mathematically. The steady state drug release rate for cylindrical reservoir systems can be described mathematically by:
                              dM          dt                =                              2            ⁢            π            ⁢                                                  ⁢            LD            ⁢                                                  ⁢            Δ            ⁢                                                  ⁢            C                                ln            ⁡                          (                                                r                  0                                                  r                  i                                            )                                                          (        1        )            in which:                dM/dt is the release rate [kg/s]        L is the length of the cylinder [m]        r0 is outer radius of the skin [m]        ri is the inner radius of the skin [m]        D is the drug in polymer diffusion coefficient [m2/s]        ΔC is the concentration gradient over the skin [kg/m3]        DΔC Is drug permeability [kg/m·s]For thin layers equation (1) can be approximated by:        
                              dM          dt                =                              2            ⁢            π            ⁢                                                  ⁢            LD            ⁢                                                  ⁢            Δ            ⁢                                                  ⁢            C                    d                                    (        2        )            in which “d” is the skin thickness [m]From equation (2) it follows that the skin thickness is proportional with the drug permeability (DΔC) and inversely proportional to drug release (dM/dt) rate:
                    d        ∝                              D            ⁢                                                  ⁢            Δ            ⁢                                                  ⁢            C                                dM            dt                                              (        3        )            Under sink conditions the concentration at the skin surface (r=r0) approaches zero and equation (3) reduces to:
                              d          ∝                                    D              ·              C                                      dM              dt                                      ,                            (        4        )            where C is the concentration in the skin at the interface (r=ri)
In WO2004/103336 the crystalline drug in the intermediate layer and the dissolved drug loaded in core and intermediate layer pass through the same skin, hence the following condition (5) holds:
                              d          ∝                                                    D                B                            ·                              C                B                                                                    dM                B                            dt                                      =                                            D              A                        ·                          C                              A                ,                s                                                                        dM              A                        dt                                              (        5        )            in which;                dMA/dt The release rate of the crystalline drug (A)        dMB/dt The release rate of the dissolved drug (B)        d Skin thickness        DA Diffusion coefficient of the crystalline drug (A)        DB Diffusion coefficient of drug (B)        CB The concentration of the completely dissolved drug        CA,s Saturation concentration of the crystalline drugFrom equation (5) follows the required concentration of the dissolved drug (B):        
                              C          B                =                                                            dM                B                            dt                                                      dM                A                            dt                                ×                                    D              A                                      D              B                                ×                      C                          A              ,              s                                                          (        6        )            
Based on mechanistic considerations it can be concluded that the concentration of the dissolved drug (CB) needed to obtain the right release for drug B, may become critically low when the saturation solubility of the crystalline drug (CA,s) is relatively low and the target release rate (dMA/dt) relatively high. Equation (6) indicates that concentration of dissolved drug (CB) in the reservoir proportionally depends on the saturation solubility and inversely on the release rate of the crystalline drug (dMA/dt). Hence CB decreases with decreasing saturation solubility CA,s and increasing release rate dMA/dt of the crystalline drug A. The drug-in-polymer diffusion coefficients in equation 6 are an intrinsic property of the polymer-drug pairs and hence these parameters may only coincidentally help to move CB in a higher direction. It can be concluded that CB and hence the amount of dissolved drug B in the delivery system, is tied by the solubility and release rate of drug A. Obviously if the amount of drug B dissolved in the reservoir is below a certain level, the release cannot be sustained over the intended duration of use. The IVRs described below are designed to overcome this and other limitations discussed above.